EP2749298B1 - 1,4,5-trisubstituiertes 1,2,3-Triazolmimetikum von RGD bzw. OGP10-14, Herstellungsverfahren und Verwendungen dafür - Google Patents

1,4,5-trisubstituiertes 1,2,3-Triazolmimetikum von RGD bzw. OGP10-14, Herstellungsverfahren und Verwendungen dafür Download PDF

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EP2749298B1
EP2749298B1 EP12382535.8A EP12382535A EP2749298B1 EP 2749298 B1 EP2749298 B1 EP 2749298B1 EP 12382535 A EP12382535 A EP 12382535A EP 2749298 B1 EP2749298 B1 EP 2749298B1
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Prior art keywords
formula
group
triazole
compound
alkyl
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English (en)
French (fr)
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EP2749298A1 (de
Inventor
Jesús Mª Aizpurua Iparraguirre
Maialen Sagartzazu Aizpurua
Iñigo Braceras Izaguirre
Francisco Javier Azpiroz Dorronsoro
Joseba Oyarbide Vicuna
Xavier Fernandez Oyon
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Euskal Herriko Unibertsitatea
Fundacion Tecnalia Research and Innovation
Centro de Investigacion Biomedica en Red en Bioingenieria Biomateriales y Nanomedicina CIBERBBN
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Euskal Herriko Unibertsitatea
Fundacion Tecnalia Research and Innovation
Centro de Investigacion Biomedica en Red en Bioingenieria Biomateriales y Nanomedicina CIBERBBN
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Application filed by Euskal Herriko Unibertsitatea, Fundacion Tecnalia Research and Innovation, Centro de Investigacion Biomedica en Red en Bioingenieria Biomateriales y Nanomedicina CIBERBBN filed Critical Euskal Herriko Unibertsitatea
Priority to ES12382535T priority patent/ES2581865T3/es
Priority to US14/655,676 priority patent/US20150353509A1/en
Priority to KR1020157020291A priority patent/KR20150123228A/ko
Priority to CN201380071626.5A priority patent/CN104955494A/zh
Priority to PCT/ES2013/070927 priority patent/WO2014102434A1/es
Priority to CA2896388A priority patent/CA2896388A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/047—Other specific proteins or polypeptides not covered by A61L31/044 - A61L31/046
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A61F2002/2835—Bone graft implants for filling a bony defect or an endoprosthesis cavity, e.g. by synthetic material or biological material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A61F2002/3093—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth for promoting ingrowth of bone tissue

Definitions

  • the present invention relates to nonpeptide mimetics of RGD (Arg-Gly-Asp) and/or, OGP 10-14 (Tyr-Gly-Phe-Gly-Gly), osteogenic compounds, containing a central 1,4,5-trisubstituted 1,2,3-triazole core and a reactive appendage appropriate to form covalent "click" bonds on the surface of materials functionalized with reactive groups including: azide, terminal alkyne, cyclooctalkyne, thiol, maleimide or thiolacid groups and to a process for the preparation of RGD and OGP 10-14 mimetics containing a 1,4,5-trisubstituted 1,2,3-triazole core.
  • nonpeptide mimetics are particularly useful for medical devices, including endosseous implants, or tissue engineering scaffold or cell culture matrix, suitable for the replacement or regeneration of human and animal organs.
  • ECM extra cellular matrix
  • RGD occurs in several ECM proteins, including vitronectin, fibronectin and osteopontin.
  • the technological interest in RGD tripeptide analogues in applications related to osteogenesis stems from their ability to regulate the out-in signaling of ECM with integrin receptors in osteoblast cells ( Kantlehner M et al. ChemBioChem 2000 1: 107-114 "Surface coating with cyclic RGD peptides stimulates osteoblast adhesion and proliferation as well as bone formation ").
  • Using RGD analogues may be beneficial to regulate bone remodeling by promoting the recruitment, attachment and differentiation of osteoblasts and osteoclasts, as demonstrated for example in osteoporosis therapy ( Chen, W. et al in Biotechnol. Lett.
  • the osteogenic growth peptide is a short naturally occurring 14-mer growth factor peptide found in serum. As a soluble peptide, OGP regulates proliferation, differentiation, and matrix mineralization in osteoblast lineage cells. Studies have demonstrated sensitivity of osteoblast lineage cells to changes in exogenous concentrations of OGP. It has also been shown in the art that only the OGP 10-14 (Tyr-Gly-Phe-Gly-Gly) pentasegment is essential for the osteogenic activity of OGP ( Chen, Y.-Ch. et al. J. Med. Chem. 2002 45: 1624-1632 "Bioactive pseudopeptidic analogues and cyclostereoisomers of osteogenic growth peptide C-terminal pentapeptide, OGP10-14 ").
  • RGD peptide analogues to the surface of bone or endosseous implants has shown to be beneficial to improve osteoblast cell adhesion (see for example Kessler H et al. Biomaterials 2003 24: 4385-4415 "RGD modified polymers: biomaterials for stimulated cell adhesion and beyond "; see also: Biltresse S. et al. Biomaterials 2005 26: 4576-4587 "Cell adhesive PET membranes by surface grafting of RGD peptidomimetics ").
  • the effectiveness of immobilized OGP to increase osteoblast cell densities and fasten their proliferation rate on OGP-stained materials has been proven “in vitro” ( Moore, N. M. et al. Biomaterials 2010 31: 1604-1611 "The use of immobilized osteogenic growth peptide on gradient substrates synthesized via click chemistry to enhance MC3T3-E1 osteoblast proliferation ").
  • RGD and OGP peptides are prone to suffer a fast deactivation by proteolytic cleavage "in vivo", leading to lowered serum concentrations in systemic applications or inactive surfaces when grafted to biomaterials.
  • RGD analogues known in the art may partially overcome this drawback, including some 1,4-disubstituted 1,2,3-triazole compounds (see Trabocchi, A. et al. J. Med. Chem.
  • Inventors have developed 1,4,5-trisubstituted 1,2,3-triazole mimetics of RGD and/or OGP 10-14 that allow to conduct in a single chemical operation the "click" bonding on the surface of a material.
  • the peptidomimetics bound in this way are stable and do not suffer degradation reactions under physiological conditions.
  • an aspect of the invention relates to a 1,4,5-trisubstituted 1,2,3-triazole mimetic of RGD and/or OGP 10-14 of formula (I): wherein:
  • Another aspect of the invention is a process for preparing the compound as defined above wherein, Y is C 6 H 4 -OH and Z is Ph, which comprises:
  • the appendage group X of the peptidomimetic is useful to bind to different materials when their surface is functionalized with reactive groups such as azide, sulfonylazide, terminal alkyne, terminal iodoalkyne, cycloalkyne, N-maleimide, N-maleimide-furan cycloadduct, thiol or thio acid.
  • reactive groups such as azide, sulfonylazide, terminal alkyne, terminal iodoalkyne, cycloalkyne, N-maleimide, N-maleimide-furan cycloadduct, thiol or thio acid.
  • Another aspect of the invention relates to a material with the surface chemically modified wherein the X group of the 1,4,5-trisubstituted 1,2,3-triazole mimetic of RGD and/or OGP 10-14 according to the 1,4,5-trisubstituted 1,2,3-triazole mimetic of RGD and/or OGP 10-14 of formula (I) as defined above is replaced by a W the group as defined above.
  • (Arg-Gly-Asp) tripeptide and OGP 10-14 (Tyr-Gly-Phe-Gly-Gly) pentapeptide have potential interest for "in vitro" tissue engineering and diagnosis technologies, or to improve the osteogenic properties of implants in human and animal therapy "in vivo".
  • a medical device made from the material described above. It can preferentially be an endosseous implant, or tissue engineering scaffold or cell culture matrices.
  • an aspect of the present invention relates to 1,4,5-trisubstituted 1,2,3-triazole mimetics of RGD and/or OGP 10-14 of formula (I) as defined above.
  • alkyl includes both saturated straight chain and branched hydrocarbon substituents.
  • C 1-20 alkyl groups Preferably, C 1-20 alkyl groups, more preferably C 1-6 alkyl groups.
  • Particularly preferred alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.
  • alkylene includes biradical hydrocarbon saturated straight chains and branched chains attaching simultaneously two molecular fragments or functional groups.
  • C 1-20 alkylene groups more preferably C 1-6 alkylene groups.
  • Particularly preferred alkylene groups include, for example, methylene, ethylene, propylene and butylene.
  • aryl includes substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 5- to 7-membered ring, more preferably a 6-membered ring.
  • R 1 is selected from the group consisting of - (CH 2 CH 2 O)rCH 2 CH 2 -; where r is an integer between 0 and 8,
  • R 2 is selected from the group consisting of -CH 2 OCH 2 CH 2 - or -CH 2 OCH 2 -
  • Y is C 6 H 4 -OH and Z is Ph.
  • Y is p-C 6 H 4 -OH and Z is Ph.
  • a material with the surface chemically modified wherein the X group of the 1,4,5-trisubstituted 1,2,3-triazole mimetic of RGD and/or OGP 10-14 according to the 1,4,5-trisubstituted 1,2,3-triazole mimetic of RGD and/or OGP 10-14 of formula (I) as defined above is replaced by a W the group as defined above.
  • the surface chemically modified wherein in the 1,4,5-trisubstituted 1,2,3-triazole mimetic Y is p-C 6 H 4 -OH and Z is Ph.
  • the material is metals, metallic alloys, polymers, ceramics or composites.
  • materials that comply with the ISO 10993 standards for evaluating the biocompatibility. Examples of materials are; Ti, Ti alloys, polyethylene, polypropylene, PET, polyamide, polyester, polyurethanes, silicones or PAEK. More preferably the material is PAEK.
  • the invention refers to a medical device wherein the device is made from the material as defined above.
  • medical device means any instrument, apparatus, appliance, material or other article, whether used alone or in combination, intended to be used for the purpose of:
  • the term “medical device” includes stents, stent grafts, catheters, guide wires, balloons, filters (e.g., vena cava filters), vascular grafts, intraluminal paving systems, pacemakers, electrodes, leads, defibrillators, joint and bone implants, spinal implants, access ports, intra-aortic balloon pumps, heart valves, sutures, artificial hearts, neurological stimulators, cochlear implants, retinal implants, and other devices that can be used in connection with therapeutic coatings, prosthetic bone implant, endooseous implant, scaffold for bone tissue regeneration.
  • filters e.g., vena cava filters
  • vascular grafts e.g., intraluminal paving systems
  • pacemakers e.g., vena cava filters
  • vascular grafts e.g., intraluminal paving systems
  • pacemakers e.g., vena cava filters
  • electrodes e.g., vena cava filters
  • Such medical devices are implanted or otherwise used in body structures, cavities, or lumens such as the vasculature, gastrointestinal tract, abdomen, peritoneum, airways, esophagus, trachea, colon, rectum, biliary tract, urinary tract, prostate, brain, spine, lung, liver, heart, skeletal muscle, kidney, bladder, intestines, stomach, pancreas, ovary, uterus, cartilage, eye, bone, joints, and the like.
  • medical device is an implant or cell culture matrix. More preferably endooseous implant or tissue engineering scaffold or cell culture matrices.
  • the invention refers a medical device wherein the medical device is an endosseous implant, or tissue engineering scaffold or cell culture matrix, suitable for the replacement of human and animal organs.
  • This intermediate product (355 mg, 0.96 mmol) was dissolved in dry MeOH and ammonium formate (302.2 mg, 4.8 mmol) and 10%-Pd-C (107.8 mg, 0.096 mmol) were added. The mixture was refluxed overnight. The product was purified by filtration over celite. Yield: 330 mg (74%).
  • EXAMPLE 12 Poly(etheretherketone) PEEK with the surface modified as cycloalkyne.
  • Compact PEEK consisted of mechanically polished PEEK-1000 semicrystalline 20 x 20 x 5 mm size square samples from Ketron (KETRON PEEK 1000, ref. 41300000, PoliFluor S.L) and medical grade implantable PEEK CLASSIX LSG compact disk samples from Invibio (PoliFluor S.L).
  • Porous PEEK consisted of disk samples (9 mm diameter/ 3 mm thin), prepared according to patent EP10382243.3 (Porous PEEK article as an implant) with VESTAKEEP ® 2000 P powder
  • the balloon flask was purged with nitrogen, then heated at 40oC for 24h, and finally refluxed for 24h. After cooling the suspenssion, the samples were extracted, rinsed successively with 10% aqueous HCl (5 x 30 mL) and ethanol (3 x 30 mL), and dried at room temperature.
  • EXAMPLE 13 Porous PEEK with the surface modified as RGD mimetic.
  • EXAMPLE 14 Compact PEEK with the surface modified as RGD mimetic.
  • EXAMPLE 15 Compact PEEK-M with the surface modified as RGD mimetic.
  • EXAMPLE 16 Compact PEEK with the surface modified as OGP mimetic.
  • EXAMPLE 17 Compact PEEK-M with the surface modified with OGP mimetic.
  • EXAMPLE 18 Compact PEEK with the surface modified with a combination of RGD and OGP peptidomimetics.
  • EXAMPLE 19 Compact PEEK with the surface modified with a combination of RGD and OGP peptidomimetics.
  • the suspension was stirred at 40oC for 24 h.

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Claims (12)

1,4,5-trisubstituierte 1,2,3-Triazolverbindung der Formel (I):
Figure imgb0018
 worin
R1 ein Biradikal ist, ausgewählt aus der Gruppe bestehend aus C1-20 Alkylen; worin 0, 1, 2, 3, 4, 5 oder 6 -CH2- Gruppen gegebenenfalls durch Gruppen ausgewählt aus -O-, -S-, -C(O)O-,-C(O)NH-, -C(O)N(C1-4Alkyl)-, -NHC(O)NH-, -NHC(O)O- ersetzt sind; und
R2 ein Biradikal ist, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus:
Alkylen; worin 0, 1, 2 oder 3 -CH2- Gruppen gegebenenfalls durch Gruppen ausgewählt aus - O- und -S- ersetzt sind; gegebenenfalls substituiert mit einer oder mehreren Gruppen ausgewählt aus Alkyl, Phenyl, Aryl; und
R3 ein Biradikal ist, ausgewählt aus der Gruppe bestehend aus: C1-6 Alkylen; gegebenenfalls enthaltend eine oder mehrere -C=C- Bindungen; gegebenenfalls enthaltend -C=C- Bindungen;
worin 0, 1, 2 oder 3 -CH2- Gruppen gegebenenfalls durch Gruppen ausgewählt aus -O- und - S- ersetzt sind; gegebenenfalls substituiert mit einer oder mehreren Gruppen ausgewählt aus C1-4 Alkyl, Phenyl, -F, -CI, -OH, -O(C1-4 Alkyl), -S(C1-4 Alkyl), -SO2Ph, -CN, -NO2, -CO(C1-4 Alkyl), -CO2H, -CO2(C1-4 Alkyl), -CONH2, -CONH(C1-4 Alkyl), -CON(C1-4 Alkyl)2; und
X eine Gruppe ist, ausgewählt aus der Gruppe bestehend aus: Azido, N-Maleimido, N-Maleimidofuran-Cycloaddukt, Thiol, Thiosäure, Azido, Sulfonylazido, Ethinyl, Jodethinyl und einer aktivierten Cyclooctinylgruppe dargestellt durch die Formeln:
Figure imgb0019
Y eine Gruppe ist, die ausgewählt ist aus -NHC(=NH)NH2 und C6H4-OH
Z eine Gruppe ist, die ausgewählt ist aus -CO2H und Ph, und
wenn Y -NHC(=NH)NH2 ist, ist Z -CO2H, und
wenn Y C6H4-OH ist, ist Z Ph.
Verbindung nach Anspruch 1, worin R1 ausgewählt ist aus der Gruppe bestehend aus - (CH2CH2O)rCH2CH2-; wobei r eine ganze Zahl zwischen 0 und 8 ist, R2 ausgewählt ist aus der Gruppe bestehend aus -CH2OCH2CH2- oder -CH2OCH2- und R3 ausgewählt ist aus der Gruppe bestehend aus -CH2CH2- oder -CH=CH-.
Verbindung nach Anspruch 1-2 worin Y -NHC(=NH)NH2 ist und Z -CO2H ist.
Verbindung nach Anspruch 1-2 worin Y C6H4-OH ist und Z Ph ist.
Verbindung nach Anspruch 4 worin Y p-C6H4-OH ist und Z Ph ist.
Verfahren zur Herstellung der Verbindungen nach Anspruch 3, das umfasst:
a) Reagieren eines Azids der Formel Q-(R1)-N3 (II) mit einem Alkin der Formel T-C≡C-(R2)-NH-PG (Schutzgruppe) (III) um ein Triazol der Formel (IV) zu erhalten,
b) Reagieren eines Triazols der Formel (IV) mit einer Verbindung der Formel S-(R3)-CO2Ra (V) oder einem Alken der Formel H2C=CH-CO2Ra (VI), um eine Verbindung der Formel (VII) zur Verfügung zu stellen,
c) Ersetzen der Q Gruppe in den Verbindungen der Formel (VII) durch eine Gruppe X, und
d) Entfernen der Schutzgruppe PG in Verbindungen der Formel (VIII) und
e) Reagieren der Zwischenprodukt-Amine mit H2NC(=NH)SO3H.
Figure imgb0020
 worin:
R1, R2, R3 und X wie in Anspruch 1 definiert sind; Ra ist H, Methyl, Ethyl, tert-Butyl oder
Benzyl; T ist H oder J; Q ist HO, Methansulfonyloxy, p-Toluolsulfonyloxy, 2-Nitrobenzensulfonyloxy, 4-Nitrobenzensulfonyloxy, Trifluormethansulfonyloxy, Cl, Br oder J; PG ist H, tert-Butoxycarbonyl, Allyloxycarbonyl oder Benzyloxycarbonyl; S in Schritt b) ist B(OH)2, Methansulfonyloxy, p-Toluolsulfonyloxy, 2-Nitrobenzensulfonyloxy, 4-Nitrobenzensulfonyloxy, Trifluormethansulfonyloxy, Cl, Br oder J.
Verfahren zur Herstellung der Verbindungen (I) nach den Ansprüchen 4-5, das umfasst:
a) Reagieren eines Azids der Formel Q-(R1)-N3 (II) mit einem Alkin der Formel T-C≡C-(R2)-(C6H4OH)-PG (IX), um ein Triazol der Formel (X) zu erhalten,
b) Reagieren eines Triazols der Formel (X) mit einer Verbindung der Formel S-(R3)-Ph (XI), um eine Verbindung der Formel (XII) zur Verfügung zu stellen,
c) Ersetzen der Gruppe Q in den Verbindungen der Formel (XII) durch eine Gruppe X, und
d) Entfernen der Schutzgruppe PG.
Figure imgb0021
 worin:
R1, R2, R3 und X wie in Anspruch 2 definiert sind; T ist H oder J; Q ist HO, Methansulfonyloxy, p-Toluolsulfonyloxy, 2-Nitrobenzensulfonyloxy, 4-Nitrobenzensulfonyloxy, Trifluormethansulfonyloxy, Cl, Br oder J; PG ist H, tert-Butoxycarbonyl, Allyloxycarbonyl oder Benzyloxycarbonyl; S in Schritt b) ist B(OH)2; PG ist Si(i-Pr)3.
Material mit einer chemisch modifizierten Oberfläche, wobei die Gruppe X der 1,4,5-trisubstituierten 1,2,3-Triazolverbindung nach Anspruch 1 bis 5 durch eine Gruppe W ersetzt ist, die dargestellt wird durch die Formeln
Figure imgb0022
Figure imgb0023
Figure imgb0024
Material mit einer chemisch modifizierten Oberfläche nach Anspruch 8, wobei die 1,4,5-trisubstituierte 1,2,3-Triazolverbindung wie gemäß Anspruch 3 definiert ist.
Material mit einer chemisch modifizierten Oberfläche nach Anspruch 8, wobei die 1,4,5-trisubstituierte 1,2,3-Triazolverbindung wie gemäß Anspruch 5 definiert ist.
Medizinische Vorrichtung, wobei die Vorrichtung aus dem wie in Anspruch 8-10 definierten Material hergestellt ist.
Medizinische Vorrichtung nach Anspruch 11, wobei die medizinische Vorrichtung ein enossales Implantat oder ein Gewebe-Entwicklungsgerüst oder eine Zellkulturmatrix ist, geeignet für den Ersatz oder die Regeneration von menschlichen und tierischen Organen.
EP12382535.8A 2012-12-26 2012-12-26 1,4,5-trisubstituiertes 1,2,3-Triazolmimetikum von RGD bzw. OGP10-14, Herstellungsverfahren und Verwendungen dafür Not-in-force EP2749298B1 (de)

Priority Applications (7)

Application Number Priority Date Filing Date Title
ES12382535T ES2581865T3 (es) 2012-12-26 2012-12-26 Mimético de 1,2,3-triazol 1,4,5-trisustituido de RGD y/u OGP10-14, procedimiento para obtenerlo y usos del mismo
EP12382535.8A EP2749298B1 (de) 2012-12-26 2012-12-26 1,4,5-trisubstituiertes 1,2,3-Triazolmimetikum von RGD bzw. OGP10-14, Herstellungsverfahren und Verwendungen dafür
KR1020157020291A KR20150123228A (ko) 2012-12-26 2013-12-26 화합물 1,4,5-삼치환된 1,2,3-트리아졸, 이를 얻기 위한 방법 및 이의 용도
CN201380071626.5A CN104955494A (zh) 2012-12-26 2013-12-26 Rgd和/或ogp10-14的1,4,5-三取代的1,2,3-三唑模拟物、其获得方法及其用途
US14/655,676 US20150353509A1 (en) 2012-12-26 2013-12-26 A Compound 1,4,5-Trisubstituted1,2,3-Triazole, Process To Obtain And Uses Thereof
PCT/ES2013/070927 WO2014102434A1 (es) 2012-12-26 2013-12-26 Mimético de 1,2,3-triazol 1,4,5-trisustituido de rgd y/u ogp10-14, procedimiento para obtenerlo y usos del mismo
CA2896388A CA2896388A1 (en) 2012-12-26 2013-12-26 A compound 1,4,5-trisubstituted1,2,3-triazole, process to obtain it and uses thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP12382535.8A EP2749298B1 (de) 2012-12-26 2012-12-26 1,4,5-trisubstituiertes 1,2,3-Triazolmimetikum von RGD bzw. OGP10-14, Herstellungsverfahren und Verwendungen dafür

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EP2749298A1 EP2749298A1 (de) 2014-07-02
EP2749298B1 true EP2749298B1 (de) 2016-04-06

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US (1) US20150353509A1 (de)
EP (1) EP2749298B1 (de)
KR (1) KR20150123228A (de)
CN (1) CN104955494A (de)
CA (1) CA2896388A1 (de)
ES (1) ES2581865T3 (de)
WO (1) WO2014102434A1 (de)

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IL117426A (en) 1996-03-10 2005-09-25 Yissum Res Dev Co Synthetic pseudopeptides having osteogenic activity and pharmaceutical compositions containing the same
SE511114C2 (sv) 1997-12-10 1999-08-09 Ericsson Telefon Ab L M Metod vid processor, samt processor anpassad att verka enligt metoden

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CN104955494A (zh) 2015-09-30
KR20150123228A (ko) 2015-11-03
EP2749298A1 (de) 2014-07-02
ES2581865T3 (es) 2016-09-07
WO2014102434A1 (es) 2014-07-03
US20150353509A1 (en) 2015-12-10
CA2896388A1 (en) 2014-07-03

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